title: Effect of sugammadex on QT/QTc interval prolongation when combined with QTc-prolonging sevoflurane or propofol anaesthesia.
abstract: BACKGROUND
  We evaluated the potential for QT/corrected QT (QTc) interval prolongation after sugammadex given with propofol or sevoflurane anaesthesia.
  
  
  METHODS
  This was a two-factorial, randomized, parallel-group study in 132 healthy subjects. Anaesthesia was maintained with sevoflurane or propofol. At ~20 min following sevoflurane/propofol initiation, sugammadex 4 mg/kg or placebo was administered. Neuromuscular blocking agents were not administered. Electrocardiograms were recorded regularly. The primary variable was the time-matched mean difference in the Fridericia-corrected QT interval (QTcF) change from baseline for sugammadex versus placebo when combined with propofol or sevoflurane. No relevant QTcF prolongation was concluded if the upper one-sided 95 % confidence interval (CI) was below the 10 ms margin of regulatory non-inferiority, up to 30 min post-study drug. Blood samples were taken for pharmacokinetic analysis. An exploratory analysis evaluated potential QT/QTc effects of neostigmine 50 μg/kg/glycopyrrolate 10 μg/kg in combination with propofol.
  
  
  RESULTS
  The estimated mean QTcF differences between sugammadex and placebo ranged from -2.4 to 0.6 ms when combined with either anaesthetic. The largest upper one-sided 95 % CI for the mean QTcF difference between sugammadex and placebo was 2 ms, occurring 2 min post-dosing. Propofol and sevoflurane resulted in mean QTcF increases exceeding 10 and 30 ms, respectively. On top of these prolongations, the effect of sugammadex was negligible at all timepoints. The mean peak sugammadex concentration was 66.5 μg/mL, with exposure similar in the sevoflurane/propofol groups. The mean QTcF changes from baseline following neostigmine/glycopyrrolate in 10 healthy subjects ranged between -1.4 and 3.6 ms.
  
  
  CONCLUSIONS
  Sugammadex 4 mg/kg does not cause clinically relevant QTc interval prolongation versus placebo when combined with propofol or sevoflurane.
authors.affiliation: Clinical Pharmacology, Merck Sharp & Dohme Corp., Rahway, NJ 07065, USA. pieter-jan.de.kam@merck.com
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: de Kam
authors.forename: Peter
authors.initials: P
authors.lastname: Grobara
authors.forename: Justin
authors.initials: J
authors.lastname: Dennie
authors.forename: Guy
authors.initials: G
authors.lastname: Cammu
authors.forename: Steven
authors.initials: S
authors.lastname: Ramael
authors.forename: Marjan L F
authors.initials: ML
authors.lastname: Jagt-Smook
authors.forename: Michiel W
authors.initials: MW
authors.lastname: van den Heuvel
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Berg
authors.forename: Pierre A M
authors.initials: PA
authors.lastname: Peeters
mesh_terms: D000328:Adult; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008738:Methyl Ethers / Q000008:administration & dosage* / Q000097:blood; D008875:Middle Aged; D010919:Placebos; D015742:Propofol / Q000008:administration & dosage* / Q000097:blood; D000077149:Sevoflurane; D000077122:Sugammadex; D047408:gamma-Cyclodextrins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D010919:Placebos; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077149:Sevoflurane; D015742:Propofol